ASIM'S WEBWORLD View: Main School Main AP Biology Chapter Guides RELATED LINKS Review Questions and Answers		AP BIOLOGY: Chapter Eighteen Outline AN OVERVIEW OF GENE MUTATION Change in Genetic Message Is Critical to Evolution Mutation: changes content of genetic message Alter identity of a nucleotide Nucleotide removed from or added to a gene Recombination: changes position of a portion of the genetic message Move gene to different chromosome Alter location of a part of a gene All DNA in Cells Results from Multitudes of Replications Mechanisms evolved to avoid errors during replication Replication errors still occur fig 18.1 Sources and Types of Mutations tbl 18.1 Point mutations Alterations in one to a few nucleotides of coding sequence Due to spontaneous pairing errors during DNA replication Result from radiation or chemical damage to DNA by mutagens Transposition Genes move from place to place on chromosome May alter expression of it or of neighboring genes Chromosomal rearrangement Occurs in eukaryotes only Large segments change location or undergo duplication How Mutagens Damage DNA Ionizing radiation High energy ejects electrons from outer shell Resultant molecule is a free radical Most atoms in cell are water Most free radicals produced from water Most damage to DNA is indirect Double-strand break Free radical breaks both DNA phosphodiester bonds Bacterial repair enzymes cannot fix this damage Eukaryotes pair damaged chromosome to homologous chromosome (evolution of meiosis) Ultraviolet radiation Lower energy, electrons not ejected, free radicals not formed Radiation absorbed only by some organic ring compounds Pyrimidine bases cytosine and thymine Double bond formed between adjacent pyrimidines Called pyrimidine dimer fig 18.2 Repair mechanisms fig 18.3 Cleave bond linking dimers Excise dimer, repair using other strand as template Blocks DNA replication if not repaired Causes mutations in skin cells Rare hereditary disorder called xeroderma pigmentosum fig 18.4 Homozygous condition results in extensive skin tumors Skin cells lack mechanism to repair even mild UV damage Chemical mutagens Direct modification of bases by various chemicals Some resemble DNA nucleotides fig 18.5 Some remove amino group from adenine and cytosine Others add hydrocarbon groups to bases Damage results in mispairing within DNA New AIDS chemotherapies use nucleotide analogs to block transcription and slow viral growth Spontaneous Mutations Not caused by radiation or chemicals Nucleotides change to other conformations, or isomers Form different kinds of hydrogen bonds Polymerase chooses wrong base to pair with isomer Slipped mispairing during chromosome pairing Sequences misalign and a portion of one strand loops out Generally transitory, self-correcting problem fig 18.6 Repair enzymes may excise unreverted loop Results in deletion of hundreds of nucleotides Creates frameshift mutation THE BIOLOGICAL SIGNIFICANCE OF MUTATION Consequence of Damage Related to Function of Altered Gene Effect Dependent on Identity of Mutated Cell In germline cells destined to be gametes Passed on to subsequent generations Raw material for natural selection and evolution In somatic cells that become the body Somatic mutations not passed on to next generation Effects only progeny of damaged cell causing cancer CHROMOSOMAL REARRANGEMENTS Most Genes Are Relatively Stable Over Time Chromosome location is important factor determining transcription Gene not transcribed if next to coiled heterochromatic region Regulation due to protein binding controlling coiling Physical Alterations to Chromosomes Effect Locations of Genes Translocations Segment of one chromosome become part of another Have important effects on gene expression Inversions Orientation of a portion of a chromosome is reversed Do not usually alter gene expression Effect recombination leading to serious problems in meiosis Problem if inversion on one homologue only After cross over event, none of gametes have complete set of genes fig 18.7 Particular genes or segments of chromosomes lost or gained Deletions harmful since they halve the number of gene copies Duplications cause imbalance and are usually harmful Aneuploidy: whole chromosome lost or gained Polyploidy: sets of chromosomes added CANCER Defined as a Disorder Causing Uncontrollable Cell Growth Growing cluster of cells called a tumor fig 18.8 Tissue may leave main mass and spread through body fig 18.9 Called metastases Cause more tumors at distant sites Tumors can occur in nearly any kind of tissue Sarcoma if connective tissue Carcinoma if epithelial tissue Many cancers are deadly tbl 18.2 Many cancers may be preventable Lung cancer linked to smoking Colo-rectal cancer linked to high meat diets Hereditary susceptibility associated with breast cancer fig 18.10 Association With Environmental Factors fig 18.11 Include ionizing radiation (x-rays) and chemicals Cancer-causing agents called carcinogens Many are also potent mutagens Some cancers may be caused by mutation Tumors also arise from viral infections CANCER AND THE CELL CYCLE Transfection Used to Study Human Tumors Nuclear DNA isolated from tumor cells Cleaved into random fragments Fragments tested for ability to induce cancer Mutation in a single gene required to induce most cancers Sometimes associated with cancer-causing virus Compare to normal, non-mutated counterparts Mutations in Oncogenes Accelerate the Cell Cycle Induction involves change in receptor activities Occurs at surface of plasma membrane Normal receptors Control activation of intracellular signalling pathways Trigger passage of G1 check point Oncogenes: cause cancer by wrongly activating cell cycle regulator All mutations are genetically dominant, Include myc and ras fig 18.12 myc stimulates production of cyclins and Cdk's ras involved with epidermal growth factor (EGF) fig 18.13 Intercellular signal that triggers cell proliferation Cancer-causing mutations reduce amount of EGF needed to do this Mutations in Tumor-Suppressor Genes Inactivate the Cell's Inhibitors of Proliferation Cell division normally blocked by proteins that prevent binding of cyclins to Cdk's Tumor-suppressor genes encode these proteins Growth-enhancing mutant alleles are genetically recessive Tumor-suppressor genes interfere with cyclin-Cdk activity Rb ties up transcription factor E2F fig 18.14 p16 and p21 reinforce tumor-suppressing role of Rb Prevent phosphorylation of Rb Bind to Cdk/cyclin complex, inhibit its kinase activity p53 is activated if DNA is damaged fig 18.15 Induces transcription of p21, binds to cyclins and Cdk Repeated sunburns induce p53 mutations, lead to skin cancer Point Mutations Can Lead to Cancer May be as little as a single-point mutation Example: human bladder cancer Induced by ras Base change from guanine to thymine Convert glycine into valine Only a Few Genes Cause Cancer Clinical form of cancer dependent on tissue where oncogene is found Genes involved with cell cycle control Proteins that they encode for are located in various parts of cell fig 18.16 Cancer Is a Multistep Mutation Process Proliferation controlled at several check points All controls inactivated to initiate cancer Induction of most cancers usually involve four genes fig 18.17 Most cancers occur after age of 40 fig 18.18 Time needed for many mutations to occur in same cells Cancer Prevention and Cure Most obvious strategy minimizes production of mutations Decrease exposure to mutagens No general cure, though remission can be effected Smoking and Cancer Definite cause and effect of smoking and lung cancer fig 18.19 Clear relationship between smoking and reduced life expectancy fig 18.20 AN OVERVIEW OF RECOMBINATION Genetic Recombination Provides Genetic Variability Defined as Change in the Position of a Gene or Gene Fragment tbl 18.3 Gene transfer Segment donated to new chromosome Example: acquisition of AIDS virus Occurs in prokaryotes and eukaryotes Most primitive process Reciprocal recombination Chromosomes trade segments Occurs only in eukaryotes Example: crossing-over Chromosome assortment Mendelian independent assortment during meiosis Occurs only in eukaryotes GENE TRANSFER Gene Position on Chromosomes Not Fixed Move to other locations on chromosomes Plasmids are small, circular auxiliary genomes Can enter and leave main genome at specific places Found primarily in bacteria Contain about 5% of bacterial genome Discovered by Lederberg and Tatum, 1947 Transposons are small fragments of the genome Migrate to other positions at random Occur in prokaryotes and eukaryotes Discovered by McClintock, 1950 Both discoveries led to Nobel Prizes, in 1958 and 1983 fig 18.21 Plasmids Formation of plasmid from circular DNA fig 18.22 Hypothetical DNA region, two copies of same gene Loop formed at this spot, transient double duplex Recombination enzymes recognize site, exchange strands Called reciprocal exchange, loop freed from circle Reintegration of plasmid on main DNA Plasmid recognition site aligns with matching sequence Recombination event elsewhere during alignment Plasmid integrated into main chromosome May integrate at any site with shared sequences Gene Transfer Among Bacteria: Conjugation Lederberg and Tatum: discovery of F (fertility) plasmid Only cells containing F acted as plasmid donors Contains recognition site and transfer promoting genes Cause formation of hollow tube called pilus Transfer of free F plasmid Contact of pilus to cell lacking pili Conjugation bridge forms between two cells F plasmid mobilized for transfer Binds to site just beneath pilus Rolling-circle replication: DNA replication occurs at binding point Replicated DNA sent to connected cell fig 18.23 Process called conjugation Transfer of integrated F plasmid Similar process where entire genome copied and transferred Process used to locate gene positions on chromosome fig 18.24 Transposition Transposons randomly move about chromosomes fig 18.25 Transposons encode transposase enzyme Selects random site and inserts transposon fig 18.26 Destination random since enzyme doesn't recognize any particular sequence Transposition relatively rare, has enormous evolutionary impact Causes mutation Insertion of mobile element destroys gene's function Called insertional inactivation May be the cause of spontaneous mutations Facilitates gene mobilization Genes located elsewhere brought to one location Generates composite plasmid with similar genes Example: resistance transfer factors Patients treated with many antibiotics at once Bacteria contain antibiotic resistance genes Surviving bacteria have many genes on one plasmid Plasmid readily passed to other bacteria Antibiotics no longer effective RECIPROCAL RECOMBINATION Chromosomes Trade Sections Important in eukaryotes Example: meiotic crossing-over Crossing Over Occurs during Prophase I of meiosis Homologous chromosomes pair side-by-side Exchange of strands at one or more locations fig 12.6 May result in physical exchange of chromosome arms Produce chromosomes differing in mutation combination Form gametes with new combination of alleles Example: giraffe Neck length gene and leg length gene on same chromosome Mutations to form long-neck allele and long-leg allele Unlikely event to get both alleles in same individual Recombination could readily cause cross-over of alleles Gene Conversion Homologues not identical thus nucleotides not complementary Called mismatch pairs Error corrected by proofreading enzymes Excise strand, fill gap complementary to other strand Produces two chromosomes with same sequence One mismatch pair lost, called gene conversion fig 18.27 Unequal Crossing Over Pairing mistake due to same sequences at many locations Homologues line up, sequence matches with a duplicate Results in unequal crossing over fig 18.28 Exchange segments of unequal length One chromosome gains copies while its homologue looses them Results in generation of hundreds of copies of a gene THE EVOLUTION OF GENE ORGANIZATION Effects of Recombination in Prokaryotes and Eukaryotes Prokaryotic genome compact with little wasted material Unequal genetic exchange deletes material fig 18.29a Minimum genome size maintained Examples Organization of lac operon fig 16.13 Overlapping reading frames in viruses Eukaryotic genome contains much duplicated material Unequal genetic exchange promotes duplication fig 18.29b Genome in constant state of flux Production of multiple copies of single gene Divergence of genes to form new genes fig 18.30 Six classes of eukaryotic DNA sequences tbl 18.4 Satellite DNA Short sequences repeated several million times Composes 4% of eukaryotic DNA Clustered around centromere or near ends fig 18.31 Remain condensed and untranscribed through cell cycle Probable structural function Transposons Repeated thousands of times Longer than satellite sequences, scattered at random Randomly jump to new locations Are transcribed but appear to have no functional role Tandem Clusters Encode cell products required in large amounts Numerous copies transcribed simultaneously Example: rRNA genes Visible as nucleolar organizer regions Disappears in division when transcription stops Reappears after division when synthesis begins Repeated many times, one after another (in tandem) Sequences similar but not precisely identical Separated from one another by spacer sequences Spacers not transcribed, dissimilar in sequence and length Multigene Families Most genes found in groups of different but related genes Far fewer genes than in tandem clusters Genes more distinctly different than tandem clusters Related in sequence Derived from a single ancestral gene Result from a series of unequal crossing-over events Dispersed Pseudogenes Pseudogenes: silent copies of a gene inactivated by mutation Result from mutations in promoters Result from frameshift mutations or small deletions Dispersed from original position within multigene family Single-Copy Genes fig 18.30 Source of new genes during evolution Result from duplication, conversion to pseudogenes Accumulation of mutations may encode new protein Initially only one copy that will eventually duplicate THE IMPORTANCE OF GENETIC CHANGE Mutation and Recombination Affect Genetic Change Genetic Change Is the Source of All Evolution